1-benzyl-4-substituted piperidines



United Sates Patent 3,161,644 LBENZYl-d-SUBSTTTUTED PHPERHDHNES PaulAdi-luau Jan .l'anssen, Vossciaar, near Tnrnheut, Belgium, assignor toResearch Lahoratorium Dr. C. lenssen NRC, a corporation of Belgium NoDrawing. Filed .lune 22, 1962, er. No. 204,624

. 9 Qlaims. C5. zen-29s This invention relates to a new series oforganic compounds generically definable as 1-benzyl-4-R -4-NHRpiperidines.

In the above general formula R stands for cyano or carbamoyl; the groupNHR stands for aniline, alkanilino, lower alkoanilino, haloanilino,alkamino and cycloalkylamino. The abbreviations alk and alko signifylower alkyl and lower alkoxy substituents containing from 1 to 6 carbonatoms. Halo represents fiuoro or, preferably, chloro. Cycloalkyl standsfor cyclopentyl or cyclohexyl. Examples of NHR groups, in addition toanilino, are: mcthylanilino, ethylanilino, propylanilino;methoxyanilino; ethoxyanilino and propoxyanilino; methylamino,ethylamino, propylamino and butylamino; cyclopentylamino,cyclohexylamino; fluoroanilino and chloroanilino.

The novel compounds of this invention are prepared by treating either apiperidone-4 or 4-hydroxypiperidine alkali metal sulfite, appropriatelyprotected at the piperidyl nitrogen by, for example, a benzyl group.Condensation of either of these with a primary amine and an alkali metalcyanide causes simultaneous introduction of the nitrile and secondaryamino groups in the piperidyl ring at the 4-position. The ketone isreacted in an aqueous organic carboxylic acid system such as acetic acid(glacial); the 4-hydroxypiperidine, or the ketone, in an aqueous loweralkanol such as methyl, ethyl or propyl alcohol in the presence of oneequivalent of hydrochloric acid.

The novel 1-benzyl-4-R -4-NHR -piperidines are useful as intermediatesfor the preparation of therapeutically active compounds. In order tomake such compounds, the novel piperidines are converted to thecorresponding amides by acid hydrolysis, which involves nucleophilicattack of the triplebond in the nitrile group, followed by rearrangementof an activated hydrogen atom of the intermediate.

Cyclization of the resulting compound is suitably effected lay treatmentwith formamide, in the absence or presence of an inorganic acid such assulfuric acid, yielding the 2,4,8-triazo-spiro(4,5)dec-Z-ene in casesWhere the secondary amino group attached to the piperidine ring isalkylsubstituted, and the 2,4,8-triaza-spiro- (4,5)decane in cases Wherethe secondary amino group is aryl-substituted. An exception occurs whenthe alkyl group is ethyl, in which case the saturated spiro compound isobtained. Reaction of the carboxamide with triethoxymethane, in thepresence-or absence of an organic carboxylic acid/organic solvent systemsuch as acetic acid/ toluene solution, invariably affords2,4,8-triaza-spiro- (4,5 dec-Z-ene.

Ring closure of the carboxamidopiperidine is alternatively accomplishedby treatment with an acylating agent, especially an anhydride of analiphatic carboxylic acid of low molecular weight. This procedure leadsto the unsaturated 2,4,8-triaza-spiro(4,5)dec-Z-ene bearing asubstituent at the 3-position identical to the aliphatic carboxylic acidresidue of the anhydride employed.

The 3,4-di-substituted 2,4,8-triaza-spiro {4,5 dec-Z-ene bearing amethyl substituent at the 3-position or the corresponding compoundunsubstituted at the 3-position may be advantageously reduced to thespiro(4,5)decane by treatment with a di-light metal hydride such aslithium aluminum hydride or sodium aluminum hydride. In the case of3-methyl substituted dec-Z-enes, debenzylation by means of hydrogenactivated by palladium-on-charcoal catalyst may be carried out before orafter saturation of the cyclic double bond. Other suitable reducingagents include hydrogen activated by platinum or nickel catalyst such asplatinum oxide or Raney nickel as well as obvious equivalents thereof.If, however, the 3-position of the dec-Z-ene is unsubstituted,saturation of the ring precedes debenzylation. In any event, thedebenzylation procedure is applicable to the 2,3-substituted andunsubstituted and 4-substitute'd compounds, except for side reactionssuch as simultaneous dehalogenation if, for example, the 4-position isoccupied by a haloaryl group.

Substituents may be introduced into the nitrogen group at the 2-positionbefore or after debenzylation. Reaction with an anhydride such as one ofthose noted above introduces an acyl group on the nitrogen. Conversely,treatment with an alkyl halide or quaternary ammonium alkylaryl halidein the presence of a strong base such as sodamide gives thecorresponding Z-aIkyI-substituted compound. A hydroxyalkyl groupmay beintroduced by reaction with the appropriate aqueous aldehyde, e.g.formaldehyde in the presence of a lower alkanol. The cyanoalkyl group isintroduced into the 2-position by treatment of the appropriatelysubstituted decane, preferably one having a benzyl group in the8-position with an unsaturated nitrile. For example, reaction withacrylonitrile introduces the cyanoethyl group in the 2-position. Thereaction is carried out in the presence of an alkali metal alkoride atslightly elevated temperature, e.g. about 50 (2., more or less, forseveral hours.

The benzyl group on the piperidine nitrogen following hydrogenolysis maybe replaced with a variety of substituents such as alkyl, aryloxyalkyl,alkaralkyl, etc. groups by treating the spiro(4,5)decane with thehalogenated reactant in the presence of an alkali metal carbonate orbicarbonate, preferably in an inert solvent medium such as a loweralkanol, e.g. methanol, ethanol, propanol or n-butanol, either singly orin admixture with another organic solvent.

If the substituent on the piperidine nitrogen is a cyanoalkyl group,reaction with an organo-metallic halide under Grignard conditionsresults in the replacement of the nitrile function with thecorresponding keto group.

As basic catalysts one may employ alkali or alkaline earth metalcarbonates, oxides or hydroxides such as sodium carbonate, or potassiumcarbonate; trialkylamines or heterocyclic amines.

Especially useful acylating agents are the anhydrides of aliphaticcarboxylic acids of low molecular weight,- e.g. acetic, propionic, orbutyric.

Organic solvents of advantage in conducting the necessary reactions ofthis invention include hexone, benzene, toluene, xylene, heptane,tetrahydrofuran, dioxane, ether. Where appropriate, water-misciblesolvents such as lower alkanols may be used, e.g. ethanol, butanol orisopropanel.

As a Grignard reagent one employs the lower alkyl magnesium halideappropriate for introduction of the desired alkyl group, e.g. methylmagnesium iodide, ethyl magnesium bromide or propyl magnesium bromide.

Aldehydes .used for introduction of the hydroxyalkyl group are thealiphatic aldehydes from 1 to 5 carbon atoms formaldehyde, acetaldehyde,propionaldehyde, butyraldehyde, and valeraldehyde.

It will be seen, therefore, that the claimed piperidines when subjectedto the above-described conversions lead to a variety of compounds whichpossess valuable pharmacological properties. These include l-oxo-2-R-3-R 4-R -8-R -2A,8-triaza spiro(4,5)decanes which have analgesicproperties. Mice injected subcutaneously with compounds of this typerespond to the hot plate test at doses from 1.0 mg./kg. upward.Mydriasis is evidenced at varying doses from 6.0 mg./kg. upward.Specific examples of these therapeutically useful decanes are thefollowing:

1-oxo-4-phenyl-8-[2-(1,4 benzodioxanyl) methyl1-2, 4,8-triaza-spiro (4,5decane.

1-oxo-4-pheny1 8 benzyl 2,4,8 triaza-spiro(4,5) decane.

1 oxo 4 phenyl-8-(4-methylbenzyl)-2,4,8-triazaspiro (4,5) decane.

1 x0 2 methyl 4-phenyl-8-benzyl-2,4,8-triazaspiro(4,5)decane.

1 oxo phenyl 8-(3-cyano-3,3-diphenylpropyl)-2,4,8- triaza-spiro 4,5)decane.

1 oxo 2 (hydroxymethyl)-4-pheny1-8-benZy1-2,4,8- triaza-spiro (4,5decane.

1 0x0 4 pheny1-8-(2-methylbenzy1)-2,4,8-triazaspiro(4,5 )decane.

1 oxo 4 phenyl-8-(4-fluorobenzyl)-2,4,8-triazaspiro (4,5) decane.

The above-mentioned decanes are those which contain in the 8-position ofthe 2,4,8-triaza-spiro(4,5)decane ring substituents such as benzyl,phenylalkyl, phenoxyalkyl and hydroxy-alkoxy-alkyl. They aredifferentiable from 2,4,8- triaza-spiro(4,5)decanes containing in the8-position a substituent characterized by possessing a carbonyl groupsuch as halobenzoyl, lower alkylbenzoyl and lower alkoxy-benzoyl.Compounds which have such substituents have entirely differentproperties from those which do not. They are neuroleptics. In miceinjected subcutaneously observable responses are obtained from 1.0mg./kg. upward in the hot plate test of Eddy et al., J. Pharmacol., 107,385 (1953) and 110, 135 (1954). Inhibition of apomorphine-inducedvomiting in dogs is observably responsive at doses as low as 0.0005mg./kg.

Compounds which are useful for this purpose are the following:

1 oxo 4 phenyl-8-[3-(4-fluorobenzoyl)-propyl]- 2,4,8-triaza-spiro (4,5decane.

1 oxo 4 phenyl-8-(3-benzoylpropyl)-2,4,8-triazaspiro(4,5)decane.

1 oxo 4 phenyl-8-[4-oxo-4-(2-thieny1)-butyl]-2,4,8- triaza-spiro (4,5decane.

dl 1 oxo 4-phenyl-8-[3-(4-fluorobenzoyl)-propyl]3-methyl-2,4,8-triaza-spiro (4,5 decane.

1 oxo 4 phenyl-Z-acetyl-S-[3-(4-fiuorobenzoyl)- propyl]-2,4,8-triaza-spiro (4,5 decane hydrochloride.

1 oxo 4 cyclohexyl-8-[3-(4-fluorobenzoyl)-propyl] 2,4,8-triaza-spiro(4,5 decane dihydrochloride.

1 0x0 2 methyl-4-phenyl 8-[3-(4-fiuorobenzoy1) propyl]-2,4,8-triaza-spiro (4,5 decane hydrochloride.

1 oxo 4 (4-methylphenyl)-8-[3-(4-fluorobeuzoyl)propyl]-2,4,8-triaza-spiro(4,5)decane.

1 oxo 4 phenyl-8-[3-(4-chlorobenzoyl)-propyl]2, 4,8-triaza-spiro (4,5decane.

It is to be understood that the conversions described here need notnecessarily follow the sequence order employed hereinabove. Norestrictions are intended to be imposed regarding the manner ofconversion, this being a matter entirely within the purview of oneskilled in the art except for steps which are chemically prohibitive,i.e. reactions which lead to undesirable degradation.

The nomenclature employed in the compounds of this application is basedupon the following nuclei:

The following examples are intended to illustrate, but not to limit, thescope of the present invention.

twelve hours at 170 C. After cooling, the reaction mixture is dividedbetween 100 parts water and 900 parts chloroform. The organic layer isseparated, dried over MgSO filtered and the filtrate is evaporated. Thesemisolid residue is stirred in 16 parts ethyl acetate. The undissolvedpart is filtered off, washed with ethyl acetate, and dried, yielding1-oxo-4phenyl-8-benzyl-2,4,8-triazaspiro(4,5)decane, melting point232238.5 C., as a white micro-crystalline powder.

Example II To a stirred mixture of 3.9 parts 1-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 3.2 parts sodium carbonate, a few crystals ofpotassium iodide in 160 parts 4-methyl-2 pentanone is added dropwise asolution of 2.8 parts 1- chloro-Z-phenylethane in 40 parts4-methyl-2-pentanone. After the addition is complete, the whole isstirred and refluxed for forty-eight hours. After cooling, 100 partswater are added. A precipitate is formed, which is filtered off,yielding a first crop of crude 1-oxo-4-phenyl-8- (Z-phenylethyl) 2,4,8triaza-spiro(4,5)decane, melting point 198.6-201 C.

From the filtrate, the organic layer is separated, dried over MgSOfiltered and evaporated. The solid residue is washed with ether anddried, yielding 1-oxo-4-phenyl- 8-(2-phenylethyl)-2,4,8triaza-spiro(4,5)decane, melting point 181184.2 C., as a beige granularpowder.

Example III A mixture of 5.4 parts 4-bromo-2,2-diphenylbutyronitrile,3.9 parts 1-oxo-4-phenyl-2,4,8-triazaspiro(4,5)decane, 3.2 parts sodiumcarbonate, a few crystals of potas sium iodide in 200 parts4-methyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling, 100 parts water are added. The aqueous layer is separatedand extracted once more with toluene. The combined organic layers aredried over MgSO filtered and the solvent is evaporated. The oily residueis dissolved in parts diisopropylether. On keeping at room temperature,1-oxo-4-pheuyl-8-(3-cyano-3,3-diphenylpropyl)2,4,8-triaza-spiro(4,5)decane is obtained, melting point 178-184 C., asa pale grey granular powder.

Example IV 20 parts 1-benzyl-4-carbamoyl-4-N-(3-methylanilino)-piperidine, 45.2 parts forrnamide are refluxed for twenty hours. Themixture is cooled to room temperature, poured in water and extractedwith 3 x 50 parts chloroform. The chloroform solutions are combined,dried over 10 parts K CO filtered and the solvent evaporated underreduced pressure on the water bath. The oily residue is taken up intoluene, treated with charcoal, filtered, concentrated under reducedpressure and dissolved in 100 parts ether with 10 parts hexone. Oncooling at -20 C., a white precipitate is formed which, after filteringwith suction and drying, yields 1-oxo-4-(3-methylphenyl)-8-benzyl 2,4,8triaza-spiro(4,5)decane, melting point 203.6-209.2 C., as a light tancrystalline powder.

Example V 15 parts 1-benzyl-4-carbamoyl-4-N-(4-methylanilino)-pipcridine and 34.5 parts formamide are refluxed and stirred for twohours. The mixture is then poured into 100 parts water, alkalinized withexcess ammonia and extracted with 3 x 50 parts chloroform. The extractis dried over 5 parts K CO filtered and evaporated to dryness underreduced pressure on a water bath. The residue is dissolved in partsethyl acetate. The precipitate which separates at once on cooling isfiltered otr', dried over K CO and Weighed. The yield of 1-oxo-4-(4-methylphenyl)-8 benzyl 2,4,8 triaza-spiro (4,5 )decane, melting point221.4222.6 C., as a grey amorphous powder.

Example VI A mixture of 415 parts l-bromo-Z-phenoxyethane, 4.4 partsl-oxo 4 phenyl 2,4,8 triaza-spiro(4,5 )decane, 3 parts sodium carbonate,a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanone isstirred and refluxed for forty-eight hours. After cooling to roomtemperature, the reaction mixture is treated with 50 parts Water and thelayers are separated. The organic layer is dried over 5 parts K COfiltered and evaporated to dryness. The solid residue is treated with 40parts diisopropylether and yields after recrystallization from 160 parts4-rnethyl- 2-pentanone1-oxo-4-phenyl-8-(Z-phenoxyethyl)-2,4,8-triaza-spiro(4,5)decane, meltingpoint 214-2l7.5 C., as light yellow needles.

Example VII A mixture of 5.8 parts Z-(brornomethyl)-1,4-benzodioxane,4.4 parts 1-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)- decane, 3 parts sodiumcarbonate, a few crystals of potassium iodide in 200 parts4-methyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling, 100 parts water are added. The organic layer isseparated, dried and filtered. On standing of the filtrate a solidprecipitated which is filtered olf, yielding crude l-oxo-4-phenyl-8-[2-( 1,4 benzodioxanyl) -methyl] 2,4,8 triazaspiro(4,5)decane.This crop is recrystallized from 100 parts toluene to yield1-oxo-4-phenyl-8-[2-(l,4-benzodioxanyl)-methyl] 2,4,8triaza-spiro(4,5)decane, melting point 215.8-218 C., as a whiteamorphous powder.

Example VIII A mixture of 4.8 pants 1-bromo-3phenoxypropane, 4.4 parts1-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 3 parts sodium carbonate,a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanone isstirred and refluxed for forty-eight hours. After cooling, 100 partswater are added. The organic layer is separated while hot, dried,filtered and evaporated. The solid residue is stirred indiisopropylether, filtered off and dried, yielding crude loxo 4 phenyl 8(3 phenoxypropyl) 2,4,8 triazaspiro(4,5)decane. This crop isrecrystallized from a mixture of 40 parts diisopropylether and 20 partstetrahydrofurane to yield 1-oxo-4-phenyl-8-(3-phenoxypropyl)-2,4,8-triaza-spiro(4,5)-decane, melting point 154.2-l56 C., as pale beigegranules.

Example IX To a mixture of 15.5 parts l-benzyl-4-carbamoyl-4-N-(4-chloroanilino)-piperidine and 50 parts forrnamide are addedportionwise 20 parts sulfuric acid 98%. After dition is complete, thewhole is refluxed for two 1. After cooling, the reaction mixture isdecomposed h 100 parts water and alkalized with a small volume ofammonium hydroxide. The whole is extracted with chloroform. The organiclayer is dried, filtered and evaporated. The residue is recrystallizedfrom ethyl acetate to yieldl-oxo-4-(4-chlorophenyl)-8-benzyl-2,4,8-triaza-spiro(4,5)decane, meltingpoint 209.52l4.8 C., as white microcrystals.

Example X A mixture of 20 parts 1-benzyl-4-carbamoyl-4-N-(3-methoxyanilino)-piperidine and 40 parts formamide is stirred andrefluxed for one and three-quarter hours. After cooling, the reactionmixture is decomposed with 20 parts ammonium hydroxide, 100 parts waterand 150 parts chloroform. The aqueous layer is separated and extractedfour times with 75 parts chloroform. The combined organic layers aredried over potassium carbonate and evaporated. The oily residue istreated with 100 parts ethyl acetate and the whole is shaken for fiveminutes. The formed precipitate is filtered ofi, washed with ethylacetate and dried, yielding crude1-oxo-4-(3-methoxyphenyl)-8-benzyl-2,4,S-triaza-spir0(4,5)decane. Thiscrop is boiled for ten minutes in 60 parts ethyl acetate and filteredwhile hot to yield crudel-oxo-4-(3-methoxyphenyi)-8-benzyl-Z,4,8-triaZa-spiro(4,5)decane. Thisfraction is recrystallized from 57 parts tetrahydrofuran. After coolingto 0 C., 1-oxo-4-(3-methoxyphenyl)-8-benzyl-2,4,8-triaza-spiro(4,5)decane is filtered off, melting point ZZZ-214 C.,as a white amorphous powder.

Example XI A mixture of 20 parts 1-benzyl-4-carbamoyl-4-N-(2-methylanilino)-piperidine and 40 parts formarnide is stirred andrefluxed for one and three-quarter hours. After cooling, the reactionmixture is decomposed with parts water and 20 parts ammonium hydroxideand extracted with parts chloroform. The obtained emulsion is clarifiedby filtering and from the filtrate the organic layer is separated, driedover potassium carbonate and evaporated. The oily residue is dissolvedin 400 parts diethylether and this solution is filtered several timesuntil clear; the filtrate is evaporated again. The oily residue isdissolved in 48 parts ether. After cooling for a few days to 15 C.,l-oxo-4-(2-methylphenyl)-8-benzyl-2,4,8-triaza-spiro(4,5)decane isobtained, melting point 151-161 C., as white shiny scales.

Example XII A mixture of 3.5 parts 2-chloromethyl-thiophene, 5 partsl-oxo-4-phenyl-2,4,8-triaza-spiro(4,5 )decane, 4 parts sodium carbonate,a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanone isstirred and refluxed for sixty hours. After cooling, 100 parts water areadded. The organic layer is separated, dried, filtered and evaporated.The solid residue is stirred in diisopropylether, filtered off anddried, yielding the product. This crop is recrystallized from a mixtureof chloroform and acetone, yieldingl-oxo-4-phenyl-8-(Z-thienylmethyl)-2,4,8-triazaspiro(4,5)decane, meltingpoint 220223 C.

Example XIII A mixture of 3.6 parts 4-fluoro-benzylchloride, 5 partsl-oxo-4-phenyl-2,4,S-triaza-spiro(4,5)decane, 4 parts sodium carbonate,a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanone isstirred and refluxed for sixty hours. After cooling, 100 parts water areadded. The organic layer is separated, dried over potassium carbonate,filtered and evaporated. The solid residue is' stirred in acetone,filtered and dried, yielding 1-oxo-4- phenyl-8-(4-fluorobenzyl)-2,4,8triaZa-spiro(4,5)decane, melting point 224234 C., as a white amorphouspowder.

Example XIV A mixture of 4.6 parts 4-methyl-benzylchloride, 5 parts1-oxo-4-phenyl-2,4,S-triaza-spiro(4,5)decane 4 parts sodium carbonate, afew crystals of potassium iodide in 200 parts 4-methyl-2-pentanone isstirred and refluxed for sixty hours. After cooling, 100 parts Water areadded; The organic layer is separated, dried, filtered and evaporated.The solid residue is stirred in diethylether and dried to yield crudeproduct. This crop isrecrystallized from 56 parts acetone, yielding1-oxo-4-phenyl-8-(4- methylbenzyl)-2,4,8 triaza-spiro(4,5)decane,melting point 182.6-185.4 C., as a pale yellow microcrystalline powder.

Example XV A mixture of 4 par-ts Z-chloromethylpyridine hydro chloride,5 part 1-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 8 parts sodiumcarbonate, a few crystals of potassium iodide in 200 parts4-methyl-2-pentanone is stirred and refluxed for sixty hours. Aftercooling, 100 parts water are added. The organic layer is separated,dried, filtered and evaporated. The solid residue is recrystallized froma mixture of acetone and chloroform, yielding.loxo-4-phenyl-8-(2-pyridylmethy1)-2,4,8-triaza spiro(4,5) decane,melting point 20l C., as a beige amorphous powder.

Example XVI A mixture of 4 parts 2,S-dimethyl-benzylchloride, 5

parts l-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 4 parts sodiumcarbonate, a few crystals of potassium iodide in 200 parts4-methyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling, 100 parts water are added. The precipitated solid isfiltered off, yielding impure product, melting point 209.4-211 C.

From the filtrate the organic layer is separated, dried, filtered andevaporated. The solid residue is stirred in diethylether, filtered offagain and dried, yielding l-o-xo- 4-phenyl-8-(2,5-dimethylbenzyl)2,4,8triaza spiro(4,5) decane, melting point 206208.4 C., as a white powder.

Example XVII Starting from 0.6 parts magnesium, 2.7 parts bromoethaneand 120 parts anhydrous ether, a solution of ethyl magnesium bromide isprepared in the usual manner. To this solution is added slowly asolution of 5 parts l-oxo- 4 phenyl 8(3-cyano-3,3-diphenylpropyl)-2,4,8-triazaspiro(4,5)decane in 200 partstoluene. After the addition is complete, most of the ether is distilledoff. The residue is stirred and refluxed for twenty hours. The reactionmixture is decomposed with 100 parts hydrochloric acid 2 N and thenstirred and refluxed for another six hours. Three layers are obtained.After separation of the supernatant toluene layer, the remaining aqueouslayer together with the oily layer is alkalized with ammonium hydroxideand the whole is extracted with chloroform. The chloroform is dried,filtered and evaporated. The solid residue is stirred in ether, filteredoff and dried, yielding crude 1 oxo4-phenyl-8-(3,3-diphenyl-4-oxohexyl)-2,4,8-triaza-spiro(4,5)decane. Thiscrop is recrystallized from a mixture of chloroform and methanol,yielding 1 oxo 4-phenyl-8-(3,3,-diphenyl-4-oxo-hexyl)-2,4,8-triaza-spiro(4,5)decane, melting point 226-228 C., as a white-greyamorphous powder.

Example XVIII To a stirred mixture of 5.1 parts 1-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 7 parts sodium carbonate, a few crystals ofpotassium iodide in 136 parts 4-methyl-2- pentanone is added dropwise asolution of 3.7 parts 2- methyl-benzylchloride in 24 parts4-methyl-2-pentanone. After the addition is complete, the whole isstirred and refluxed for forty-eight hours. After cooling, 150 partswater are added. The precipitate is filtered off, yielding crude1-oxo-4-phenyl-8-(Z-methylbenzyl)-2,4,8-triazaspiro (4,5 )decane. Fromthe filtrate, the aqueous layer is separated and extracted once morewith 40 parts 4- methyl-Z-pentanone. The combined organic layers aredried over potassium carbonate and evaporated. The solid residue isstirred in 80 parts diisopropylether, filtered off again and dried,yielding a second fraction of impure 1 oxo4-phenyl-8-(Z-methylbenzyl)-2,4,8-triaza-spiro- (4,5 )decane. Thecombined fractions are recrystallized from 56 parts4-methyl-2-pentanone. After cooling to C., 1oxo-4-phenyl-8-(Z-methylbenzyl)-2,4,8-triazaspiro (4,5 )decane isobtained, melting point 217-2l9 C., as white shiny crystals.

Example XIX A mixture of 3.6 parts 3 methyl-benzylchloride, 5 parts 1oxo 4-phenyl-2,4,8-triaza-spiro(4,5)decane, 4 parts sodium carbonate, afew crystals of potassium iodide in 200 parts 4-methyl-2-pentanone isstirred and refluxed for forty-eight hours. After cooling the reactionmixture, 100 parts water are added. The whole is stirred and the formedprecipitate is filtered off, yielding crude 1 oxo 4phenyl-8-(3-methylbenzyl)-2,4,8-triaza-spiro (4,5)decane. This crop isrecrystallized from 80 parts 4 methyl 2 pentanone, yielding1-oxo-4-phenyl-8-(3- mcthylbenzyl) 2,4,8 triaza spiro(4,5)decane,melting point 220-225 C., as white amorphous powder.

Example XX To a stirred mixture of 5.1 parts 1-oxo-4-phenyl-2,4,8-

triaza-spiro(4,5)decane, 7 parts sodium carbonate and a few crystals ofpotassium iodide in 136 parts 4-methyl- Z-pentanone is added dropwise asolution of 5.25 parts l-bromo-3-phenylpropane in 24 parts4-methyl-2-pentanone. After the addition is complete, the whole isstirred and refluxed for forty-two hours. After cooling, 150 parts waterare added. The aqueous layer is separated and extracted once more withabout 40 parts 4-methyl- Z-pentanone. The combined organic layers aredried over potassium carbonate and evaporated. The solid residue isstirred in about parts diisopropylether and filtered off again. It isrecrystallized from 56 parts 4- methyl-Z-pentanone. After cooling to 0C., the precipitate is filtered off and dried for two hours at C.,yielding l-oxo-4-phenyl-8- 3-phenylpropyl) -2,4,8-triazaspiro(4,5)decane, melting point 169.6-l70.8 C., as a grey amorphous powder.

Example XXI A mixture of 7.5 parts 4-bromo-2,2-diphenyl-butyronitrile, 5parts 1 oxo 4 methyl-2,4,8-triaza-spiro (4,5) decane hydrochloride, 8parts sodium carbonate and a few crystals of potassium iodide in 320arts 4-methyl-2-pentanone is stirred and refluxed for seventy-six hours.The reaction mixture is filtered and the filtrate is evaporated. Thesolid residue is recrystallized from 80 parts 2-propanol. Theprecipitate is filtered off, washed with ether and dried, yieldingl-oxo-4-methyl-8-(3-cyano-3,3-diphenylpropyl)-2,4,8 triazaspiro(4,5)decane, melting point l17.4l2l C., as a White powder.

Example XXII Example XXIII A mixture of 7.5 parts4-bromo-2,2-diphenyl-butron.itrile, 5 parts1-oxo-4-(3-methylphenyl)-2,4,8-triaza-spiro- (4,5 )decane, 4 partssodium carbonate and a few crystals of potassium iodide in 200 parts4-methyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooli parts water are added. The organic layer is separated, driedover magnesium sulfate, filtered and evaporated. The residue isrecrystallized from 80 parts boiling diethylether. yielding l-oxo 4(3-methylphenyl)-8- (3 cyano 3,3-diphenylpropyl)-2,4,8-triaza-spiro(4,5)decane, melting point 206212 C., as a pale brown amorphous powder.

Example XXIV A mixture of 7.5 parts 4-bromo-2,2-diphenylbutyronitrile, 5parts 1-oxo-4-(4-methylphenyl)-2,4,8-triaza-spiro- (4,5)decane, 4-partssodium carbonate and a few crystals of potassium iodide in 200 parts4-rnethyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling, 150 parts water are added. The organic layer isseparated, dried, filtered and evaporated. The solid residue is stirredin diethylether, filtered off again and dried, yielding1-oxo-4-(4-methylphenyl)-8-(3-cyano-3,3- diphenylpropyl) 2,4,8 triazaspiro(4,5)decane, melting point 205211 (3., as a white amorphous powder.

Example XXV mixture of 4.5 parts 4-bromo-2,2-diphenylbutyronitrlle, 4.5parts l-oxo-4-cyclohexyl-2,4,fi-triazaspiro(4, 5)decane dihydrochloride,6 parts sodium carbonate and a few crystals of potassium iodide in 200parts 4-methy1- Z-pentanone is stirred and refluxed for seventy-twohours. The reaction mixture is filtered and the filtrate is evaporated.The residue is dissolved in water and the whole is extracted withchloroform. The organic layer is dried over sodium sulfate andevaporated. The residue is dissolved in a mixture of 40 parts 2-propanoland 40 parts diisopropylether. After keeping at room temperature, twofractions are obtained, a first crop of l-oxo-4-cyclohexyl 8 (3 cyano3,3 diphenylpropyl) 2,4,8 triaza-spiro(4,5),decane contaminated withsome of its hydrobromide and a second crop of l-oxo-4-cyclonexyl-8- (3cyano 3,3 diphenylpropyl) 2,4,8 triaza-spiro- (4,5 )decane, meltingpoint 172.5-175 C., as a pale yellow, granular powder.

Example XXVI To a stirred mixture of 5.5 parts l-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 7.5 parts sodium carbonate and a few crystalsof potassium iodide in 136 parts 4-1nethyl- 2-pentanone is addeddropwise a solution of 3.5 parts l-chloro-Z(Z-hydroxyethoxy)-ethane in24 parts 4-methyl-Z-pentanone. After the addition is complete, the Wholeis stirred and refluxed for forty-eight hours. After cooling, 150 partsWater are added. The aqueous layer is separated and extracted once morewith 80 parts 4- methyl-Z-pentanone. The combined organic layers aredried over potassium carbonate and concentrated to a volume of 70 parts.After cooling this residue for one hour at C.,l-oxo-4-phenyl-8-[2-(2hydroxyethoxy)- ethyl]2,4,8-triaza-spiro(4,5)decane is obtained, melting point 197.6-234 C.(dec.), as a biege amorphous powder.

Example XXVI] To a stirred mixture of 0.6 part lithium aluminum hydride,48 parts benzene and 24 parts tetrahydrofurane are added, portionwise,5.4 parts of 1-oxo'3-methyl-4- phenyl 8 benzyl 2,4,8 triazaspiro(4,5)dec 2 ene. After the addition is complete, the whole isstirred and refluxed for twenty hours. After cooling, the reactionmixture is decomposed by successive addition of 50 parts water and 100parts hydrochloric acid 1 N. Then there are added 6 parts tartaric acid.The solution is alkalized with ammonium hydroxide and extracted withchloroform. The organic layer is separated, dried over magnesiumsulfate, filtered and evaporated. The oily residue is dissolved in aboiling mixture of 20 parts ethyl acetate and 160 parts diethylether andgaseous hydrogen chloride is introduced into the solution. Theprecipitated hydrochloride is filtered off and recrystallized from 68parts boiling 2-propanol, yielding crude hydrochloride. This crop isdissolved in water. The aqueous solution is alkalized with ammoniumhydroxide. The separated free base is filtered off and recrystallizedfrom 24 parts boiling 4-methyl-2-pentanone. After cooling, dl-1-oxo-3-methyl-4-phenyl-8-benzyl-2,4,8-triaza-spiro (4,5 decane is filtered off,melting point 150151.8 C., as a white granular powder.

Example XXVIII A mixture of 5 parts 1-bromo-2-phenoxyethane, 5 parts 1oxo 4 (4 methylphenyl) 2,4,8 triaza-spiro(4,5)- decane, 4 parts sodiumcarbonate and a few crystals of potassium iodide in 200 parts4amethyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling, 100 parts water are added. The organic layer isseparated, dried, filtered and on keeping the filtrate at roomtemperature, the product is filtered off. This crop is recrystallizedfrom 48 parts 4-methyl-2-pentanone, yielding 1 oxo 4 (4 methylphenyl) 8(2 phenoxyethyl)- 2,4,8-triaza-spiro(4,5)decane, melting point 177-1775C., as colorless shiny crystal needles.

Example XXIX A mixture of 5 parts 1-oxo-4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)decane, 10 parts acetic acid anhydride and 40 partstoluene is stirred and refluxed for fifteen hours. After cooling, thereaction mixture is alkalized with ammonium hydroxide. The organic layeris separated, dried over magnesium sulfate, filtered and the filtrate isconcentrated to a volume of parts. To this residue are added 56 partsdiethylether. After keeping at room temperature,1-oxo-2-acetyl-4-phenyl-8-benzyl- 2,4,8-triaza-spiro(4,5)decane isfiltered olf, melting point 128-130" C., as a white amorphous powder.

Example XXX A mixture of 6.4 parts l-oxo-4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)-decane, 0.98 part sodamide and parts anhydrous tolueneis stirred and refluxed until no more ammonia is evolved (in the courseof about thirty minutes). After cooling, 5.4 partsN,N,N-trimethylaniliniumbromide are added. Then the whole is stirred andrefluxed for sixteen hours. After cooling, parts water are added. Theorganic layer is separated, dried over magnesium sulfate and filteredand evaporated. To the oily residue are added 50 parts water and thewhole is evaporate again. This treatment is repeated three times toremove the dimethylaniline formed during the reaction. The residualwater is removed by repeated azeotropic distillation with 40 parts4-methyl-2-pentanone. The oily residue is then dissolved in a mixture of16 parts ethyl acetate and 40 parts diethylether. After keeping at roomtemperature, l-oxo-2-methyl-4phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)decane is filtered off, melting point 138-1405 C., aswhite crystals. On further cooling the mother liquor at 0 C., a secondfraction of less pure 1 oxo 2 methyl 4 phenyl 8 benzyl 2,4,8triaza-spiro(4,5)decane is obtained, melting point 136- 184 C.

Example XXXI A mixture of 6 parts1-oxo-4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)decane, 10 partsformaline 37% and 48 parts Z-prcpanol is stirred and refluxed forsixteen hours. The reaction mixture is kept at room temperature,yielding 1-oxo-2- (hydroxymethyl) -4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)decane, melting point 1714-173 C., as aWhite amorphous powder. On further keeping the filtrate at roomtemperature, a second fraction of1-oxo-2-(l1ydroxymethyl)-4-phenyl-8-benzyl-2,4,8 triaza spiro (4,5)decane is filtered 01f, melting point 169-17() C. (dec.).

Example XXXIH A mixture of 4.5 parts l-broino-2-phenoxyethane, 6.7 parts1-oxo-4-cyclohexyl-2,4,'8-triaza-spiro(4.5)decane dilrydrochloride, 8.5parts sodium carbonate and a few crystale of potassium iodide in 240parts 4-methyl-2-pentanone is stirred and refluxed for forty-eighthours. The reaction mixture is filtered and evaporated. The solidresidue is recrystallized from acetone, yielding 1-oxo-4cyclohexyl- 82-phenoxyethyl -2,4,8-triaza-spiro (4,5 decane, melting point 161-1625C., as pale beige crystals.

Example XXXIV A mixture of 6.4 parts 1-o-xo-4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)decane, 1 part sodamide and 40 parts anhydrous tolueneis stirred and refluxed for one hour. Then there is added dropwise asolution of 2.2 parts ethylbromide in 40 parts anhydrous toluene to therefluxing solution. After the addition is complete, stirring andrefluxing is continued for three hours. After cooling, the reactionmixture is decomposed with water. The aqueous layer is separated andextracted once more with toluene. The combined organic layers areseparated, dried over magnesium sulfate, filtered and evaporated. Thesemisolid residue is dissolved in 160 parts ether. The solution isfiltered and gaseous hydrogen chloride is introduced into the filtrate.The precipitated solid hydrochloride is filtered off and recrystallizedfrom 24 parts Z-propanol to yield l-oxo-2-ethyl-4-phenyl-8-benzyl-2,4,8triaza spiro (4,5)decane hydrochloride, melting point 234-238" C., as agrey-white granular powder.

Example XXXV A mixture of 72 partslbenzyl-4-carbamoyl-4-N-(ethylamino)-piperidine, 177 parts formamide and44 parts sulfuric acid 98% is stirred and refluxed for one hour. Aftercooling, 200 parts water are added. The whole is alkalized with ammoniumhydroxide and extracted with chloroform. The organic layer is dried oversodium sulfate, filtered and evaporated. The residue is dissolved in 120parts ethyl acetate. After cooling for three hours at 15 C., 3 parts ofan unidentified solid are filtered oif. After further cooling of themother liquor for four days at C., l-oxo-4-ethyl-8-benzyl 2,4,8triaza-spiro(4,5)- decane is obtained, melting point l39145.4 C., as agrey-white granular powder.

Example XXXVI A mixture of 3.8 parts cinnamylchloride, 5 parts l-oxo-4-phenyl-2,4,8 triaza spiro(4,5 )decane, 4 parts sodium carbonate and afew crystals of potassium iodide in 200 parts 4-methyl-2-pentanone isstirred and refluxed for forty-eight hours. After cooling, 100 partsWater are added. The organic layer is separated, dried, filtered andevaporated. The residue is dissolved in diethylether and filtered. Aftercooling at room temperature, 2.5 parts less pure product are obtained.This crop is recrystallized from 160 parts ether, yieldingl-oxo-4-phenyl-8- cinnamyl 2,4,8 triaza spiro (4,5 )decane, meltingpoint l7ll72.2 C., as pale beige crystals.

Example XXX VII A mixture of 5 partsl-oxo-4-phenyl-8-(3-cyano-3,3-diphenylpropyl)-2,4,8-triaza-spiro(4,5)decane,10 parts acetic acid anhydride and 80 parts anhydrous toluene is stirredand refluxed for fifteen hours. The reaction mixture is alkalized withammonium hydroxide. The organic layer is separated, dried, filtered andevaporated. The solid residue is recrystallized from 80 parts4-methyl-2- pentanone, to yield 1oxo-2-acetyl-4-phenyl-8(3cyano-3,3-diphenylpropyl)-2,4,8-triaza spiro(4,5 )decane, melting point2l9220.5 C., as a pale yellow amorphous powder.

Example XXXVIII A mixture of 4.6 parts lchloro-4-phenoxybutane, 5 parts1-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 4 parts sodium carbonateand a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanoneis stirred and refluxed for forty-eight hours. After cooling, 100 partswater are added. The organic layer is separated, dried, filtered andevaporated. The solid residue is recrystallized from 240 partsdiethylether to yield the crude product. This crop is recrystallizedfrom 80 parts 4-methyl-2-pentanone, yieldingl-oxo-4-phenyl-S-(4-phenoxybutyl)-2,4,8 triazaspiro(4,5)decane, meltingpoint 85ll2 C. (dec.), as a pale yellow granular powder.

EXAMPLE XXXIX To a mixture of 6.4 parts 1oxo-4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)decane, 1.3 parts acrylonitrile and parts dioxaneis added dropwise a solution of sodium ethoxide, prepared from 0.35 partsodium in 8 parts parts 4-methyl-2-pentanone.

ethanol. After the addition is complete, the whole is heated to 50 C.While maintaining this temperature, the mixture is stirred for threehours. After cooling, 50 parts water are added. The whole is extractedtwice with 240 parts ether. The organic layer is separated, dried overpotassium carbonate and gaseous hydrogen chloride is introduced into it.An oily hydrochloride is obtained. The solvent is decanted and the oilyresidue is dissolved in water. The aqueous solution is alkalized withsodium hydroxide and extracted with ether and chloroform. The combinedorganic solutions are dried over magnesium sulfate and gaseous hydrogenchloride is introduced into it. A sticky hydrochloride is obtained,which is dissolved in parts boiling 2-propanol. After keeping forforty-eight hours at room temperature, the crude product is obtained.This crop is recrystallized from a mixture of 48 parts acetone and 8parts 2-propanol. After cooling overnight at 20 C., 1-oxo-2-(Z-cyanoethyl) 4 phenyl-8-benzyl-2,4,8-triaza-spiro(4, 5 )decanehydrochloride is obtained, melting point 217.8- 219 C., as purple shinycrystals.

EXAMPLE XL A mixture of 6.1 parts 1-bromo-3,3-diphenylpropane, 4.6 parts1-oxo-4-phenyl-2,4,S-triaza-spiro(4,5)decane, 3.2 parts sodium carbonateand a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanoneis stirred and refluxed for sixty hours. After cooling, 50 parts waterare added. The organic layer is separated, dried over potassiumcarbonate and evaporated. The oily residue is dissolved in 40 partsacetone. This solution is poured into 400 parts diisopropylether. Afterfiltration gaseous hydrogen chloride is introduced into the filtrate.The precipitated hydrochloride is filtered off and dried, yielding 5.2parts crude salt. This crop is recrystallized from a boiling mixture of80 parts 2-propanol and 40 parts acetone. The undissolved part isfiltered off. After cooling the filtrate for three hours at 20 C.,1-0xo-4- phenyl 8 (3,3-diphenylpropyl)-2,4,8-triaza-spiro(4,5) decanehydrochloride is filtered off, melting point 247- 251 C., as a paleyellow amorphous powder.

EXAMPLE XLI A mixture of 4.3 parts 3-chloro-l,l-diphcnylpropanol, 4.6parts 1-oXo-4-phenyl-2,4,S-triaza-spiro(4,5)decane, 3.2 parts sodiumcarbonate and a few crystals of potassium iodide in parts4-methyl-2-pentanone is stirred and refluxed for sixty hours. Aftercooling, 50 parts water are added. The organic layer is separated, driedover potassium carbonate and evaporated. The solid residue is trituratedin 24 parts acetone, yielding the crude product. This crop isrecrystallized from a boiling mixture of 80 parts acetone and 8 parts2-propanol. After cooling overnight at 20 C., l-oxo-4-phenyl-8-(3,3-diphenyl 3 hydroxypropyl)-2,4,8-triaza-spiro (4,5) decane isobtained, melting point 226231.5 C., as a white amorphous powder.

EXAMPLE XLII To a stirred and refluxing solution of 4.6 parts l-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 3.2 parts sodium carbonate and afew crystals of potassium iodide in parts 4-methyl-2-pentanone is addeddropwise a solution of 4.4 parts 2-(2-chloroethyl)-l,4-benzodioxane in40 After the addition is complete the whole is stirred and refluxed forsixty-five hours. After cooling, 50 parts Water are added. The organiclayer is separated, dried over potassium carbonate, filtered andevaporated. The oily residue is dissolved in a mixture of 120 partsacetone and 120 parts diisopropylether. This solution is filtered andgaseous hydrogen chloride is introduced into the filtrate. The solidhydrochloride is filtered otf, boiled in 320 parts 4-methyl-2-pentanone, filtered off again and dried, yielding the crude product.This crop is recrystallized from 64 parts 2- propanol. On standing atroom temperature a first fraction of less pured1-l-oxo-4-phenyl-8-{2-[2-(1,4-henzodioxanyl) ]-ethyl}-2,4,8triaza-spiro(4,5 decane chloride is obtained, melting point 154 220 C.On further coolingv the filtrate at C., another fraction of puredl-1-oxo-4-phenyl-8-{2[2-(1,4 benzodioxanyD]ethyl}-2,4,8-triaza-spiro(4,5)decane hydrochloride is filtered 01f,melting point 14l.6+202 C. (dec.), as a brown-yellow amorphous powder.

EXAMPLE XLIII A mixture of 3.2 parts 4-chloro-p-fiuoro-butyro phenone,3.5 parts 1-oxo-4-phenyl-2,4,8-triaza-spiro(4,5) decane, 2 parts Na COand 0.1 part KI in 200 parts hexone is refluxed with stirring for fiftyhours. The mixture is cooled to room temperature, 200 parts water areadded and the layers are separated. The organic layer is dried over 10parts MgSO filtered and the solvent removed under reduced pressure onthe water bath. The residue is treated with 50 parts diisopropylether.The precipitate is filtered on a Buchner filter and recrystallized from20 parts hexone at room temperature. The solid is filtered off and driedto yield l-oxo-4-phenyl- 8-[3-(4-fluorobenzoyl)-propyl] 2,4,8triaza-spiro(4,5) decane, melting point 190193.6 C., as a light brownamorphous powder.

EXAMPLE XLIV To a stirred mixture of 5.1 parts 1-oxo-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 7 part-s sodium carbonate and a fewcrystals of potassium iodide in 136 parts 4- methyl-Z-pentanone is addeddropwise a solution of 4.8 parts 4-chlorobutyrophenone in 24 parts4-methyl-2-pentanone. After the addition is complete, the whole isstirred and refluxed for forty-eight hours. After cooling, 150 partswater are added. The aqueous layer is separated and extracted once morewith 40 parts 4- methyl-Z-pentanone. The combined organic layers aredried over potassium carbonate and evaporated. The solid residue isrecrystallized from about 56 parts 4- methyl-Z-pent-anone. After coolingto 0 C., 1-oxo-4- pheny1-8-(3-benzoylpropyl) 2,4,8 triaza-spiro (4,5)dec ane is obtained, melting point l73.8l77.6 C., as a pale brownamorphous powder.

Example XLV A mixture of 4.2 parts of 4-chloro-butyrothienone, parts of1-oxo4-phenyl-2,4,8-triaza-spiro(4,5)decane, 4 parts sodium carbonateand a feW crystals of potassium iodide in 200 parts 4-methyl-2-pentanoneis stirred and refluxed for forty-eight hours. After cooling thereaction mixture, 100 parts Water are added. The undissolved part isfiltered olt to yield l-oxo-4-phenyl-8-[4-oxo-4-(2- thienyl) butyl]2,4,8-triaZa-spiro(4,5)decane, melting point 1725-177" C., as a beigegranular powder.

From the filtrate the organic layer is separated, dried, filtered andevaporated. The residue is recrystallized from 20 parts4-methyl-2-pentanone, yielding crude 1- oxo 4-phenyl-8-[4-oxo-4-(2thienyl)-butyl]-2,4,8-triazaspiro(4,5)decane, melting point 160.6l73 C.(dec.).

Example XLVI A mixture of 5 parts 4-chloro-4-fiuorohutyrophenone, 5parts 4-(3-methylphenyl) -1-oxo-2,4,8-triaza-spiro(4,5 decane, 4 partssodium carbonate, and a few crystals of potassium iodide in 200 parts4-methyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling the reaction mixture, 100 parts Water are added. Theorganic layer is separated, dried, filtered and evaporated. The solidresidue is stirred in diethylether, filtered off again and dried toyield crude 1-oxo-4-(3-me-thylphenyl)- S [3 (4fluorobenzyl)-propyl]-2,4,8-triaza-spiro(4,5)- decane. This crop isrecrystallized from a mixture of diisopropylether and tetrahydrofurane,yielding 1-oxo-4- (3 methylphenyl)-8-[3-(4-luorobenzoyl)-propyl]-2,4,8-

hydro- 1d triaza-spiro(4,5)decane, melting point l80.8l82.6 C., as apale beige amorphous powder.

Example XLVH A mixture of 5 parts 4-chloro-4-fluoro-butyrophenone, 5par-ts 4-(4-methylphenyl)-1-oxo-2,4,8-triaza-spiro-(4,5 decane, 4 partssodium carbonate and a few crystals of potassium iodide in 200 parts 4-nethyl-2-pentanone is stirred and refluxed for forty-eight hours. Aftercooling, 50 parts water are added. The organic layer is separated,dried, filtered and the filtrate is evaporated. The solid residue isstirred in diethylether, filtered off again and dried, yielding thecrude product. This crop is recrystallized from a mixture of 40 partsdiisopropylether and 40 parts tetrahydrofurane, yielding l oxo 4(4-metl1ylphenyl) 8 [3(4-fluorobenzoyl)-propyl]-2,4,8-triazaspiro(4,5)decane, melting point178-1808 C., as a white amorphous powder.

Example XLVIII A mixture of 3 parts 4,4'-dichloro-butyrophenone, 3.5parts 1 oxo 4-phenyl-2,4,S-triaza-spiro(4,5)decane, 4 parts sodiumcarbonate and a few crystals of potassium iodide in 200 parts4-methyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling, 100 parts water are added. The organic layer isseparated, dried, filtered and evaporated. The solid residue is firstrecrystallized from 40 parts acetone and then from 24 parts4-methyl-2-pentanone, yielding l-oxo-4-phenyl-8-[3-(4- chlorohenzoyl)propyl] 2,4,8-triaza-spiro(4,5)decane, melting point 202203.8 C., as apale brown amorphous powder.

Example XLIX A mixture of 5 parts 4-chloro-4-fluoro-butyrophenone, 5parts l-oxo-4-methyl-2,4,S-triaza-spiro(4,5)decane hydrochloride, 8parts sodium carbonate and a few crystals of potassium iodide in 320parts 4-methyl-2-pen-tanone is stirred and refluxed for forty hours. Asecond portion of 5 parts 4-chloro-4-fiuoro-butyrophenone is added andthe whole is stirred and refluxed for another twenty-six hours. Thereaction mixture is filtered and the filtrate is evaporated. The solidresidue is recrystallized from parts Z-propanol. After keeping at roomtemperature, the crude free base ofl-oxo-4-metl1yl-8-[3-(4-fiuorobenzoyl) propyl]2,4,8-triaza-spiro(4,5)decane dihydrochloride is filtered olf. This cropis dissolved in chloroform. The organic layer is washed with water,dried over potassium carbonate and evaporated. The residue is dissolvedin 2-propanol and gaseous hydrogen chloride is introduced into thesolution. The precipitated hydrochloride is filtered oil and dried,yielding 1- oxo 4 methyl 8 [3-(4-fiuorobenzoyl)-propyl]-2,4,8-triaZa-spiro(4,5)decane dihydrochloride, melting point 203.62l2 C., as agrey-white amorphous powder.

Example L To a mixture of 2.8 parts dl-l-oxo-3-methyl-4-phenyl-2,4,8-triaza-spiro(4,5)decane, 1.8 parts sodium carbonate, and a fewcrystals of potassium iodide in 80 parts 4-rnethyl-2-pentanone is addeddropwise a solution of 3 parts 4-chloro-4-fiuoro-butyrophenone in 80parts 4- methyl-Lpentanone. After the addition is complete, the Whole isstirred and refluxed for forty-eight hours. After cooling, parts waterare added. The organic layer is separated, dried over magnesium sulfate,filtered and the filtrate is concentrated to a volume of 60 parts,whereupon a solid is precipitated. It is filtered off and dried to yielddll-oxo-3-methyl-4-phenyl-8- 3- (4-fluorobenzoyl)propyl]-2,4,8-triaza-spiro(4,5)decane, melting point 148- 149.6 C., as awhite amorphous powder.

Example Ll To a stirred mixture of 5.75 parts1-oxo-4-(4-methoxyphenyl)-2,4,8-triaza-spiro(4,5)decane, 7 parts sodiumcarbonate and a few crystals of potassium iodide and 136 parts4-methyl-2-pentanone is added dropwise a solution of 5.3 parts4-chloro-4'-fluoro-butyrophenone in 24 parts 4-methyl-2pentanone. Afterthe addition is complete, the whole is stirred and refluxed fortwenty-four hours. Then there is added a second portion of 2.65 parts 4-chloro-4'-fluoro-butyrophenone dissolved in 24 parts 4-methyl-Z-pentanone and after this addition is complete, the whole isstirred and refluxed for another forty-eight hours. After cooling 150parts water are added. The organic layer is separated, dried overpotassium carbonate and evaporated. The solid residue is stirred in 80parts diisopropylether, filtered off and dried, yielding crude 1- x0 4(4-methoxyphenyl)-8-[3-(4-fluorobenzoyl)-propyl]-2,4,8-triaza-spiro(4,5)decane. This fraction is recrystallizedtwice from 4-methyl-2-pentanone (respectively from 32 parts and 24parts), yielding l-oxo-4-(4- methoxyphenol) 8[3-(4-fluorobenzoyl)-propyl]-2,4,8- triaza-spiro(4,5)decane, meltingpoint 163-165 C,, as a pale yellow crystalline powder.

Example LII A mixture of 4.8 parts 4-chloro-4'-methyl-butyrophenone,parts 1-oxo-4-phenyl-2,4,8-triaza-spiro-(4,5)decane, 4 parts sodiumcarbonate and a few crystals of potassium iodide in 200 parts4-methyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling, 100 parts water are added. The organic layer isseparated, dried over potassium carbonate, filtered and the filtrate isconcentrated under reduced pressure, whereupon a solid is precipitated.It is filtered off, washed with diethylether and dried, yielding1-oxo-4-phenyl-8- [3 (4 methylbenzoyl) propyl] 2,4,8 triaza spiro-(4,5)decane, melting point l90.6l93.8 C., as a white amorphous powder.

Example LIIl A mixture of 5 parts 1-oxo-4-phenyl-8-[3-(4-fluorobenzoyl)propyl] 2,4,8 triaza spiro(4,5)decane, parts acetic acid anhydride and80 parts toluene is stirred and refluxed for sixteen hours. Aftercooling, the reaction mixture is alkalized with ammonium hydroxide. Theorganic layer is separated, dried, filtered and evapo rated. The oilyresidue is dissolved in diethylether. Then gaseous hydrogen chloride isintroduced into the solution. The precipitated hydrochloride is filteredoff and recrystallized from 40 parts 4-rnethyl-2-pentanone, yielding loxo 2 acetyl 4 phenyl 8 [3 (4- fiuorobenzyl) propyl] 2,4,8 triazaspiro(4,5)decane hydrochloride, melting point 1882l2.5 C. (dec.), aswhite granules.

Example LIV A mixture of 4 parts 4-chloro-4'-fiuoro butyrophenone, 3.5parts l-oxo-4-(2-propyl)-2,4,8-triaza-spiro(4,5)decane, 6.36 partssodium carbonate and a few crystals of potassium iodide in 160 parts4-rnethyl-2-pentanone is stirred and refluxed for twenty-four hours.Then a second portion of 2 parts 4-chloro-4'-fluoro-=butyrophenone isadded and the whole is stirred and refluxed for another thirty-sixhours. The reaction mixture is filtered while hot and the filtrate isevaporated. The oily residue is dissolved in a mixture of 160 partsether and 80 parts 4-methyl-2-pentanone. Gaseous hydrogen chloride isintroduced into the solution. The precipitated solid hydrochloride isfiltered off, yielding the product. This crop is recrystallized from amixture of 80 parts ethanol (denatured), 80 parts acetone and 320 partsmethanol. After cooling for three hours at l5 C., the precipitated solidis filtered off. This crop is dried for thirty hours at 70 C., yeldingl-oxo-4-(2-propyl)-8-[3-(4- fluorobenzoyl) propyl] 2,4,8 triazaspiro(4,5)decane dihydrochloride hemihydrate, melting point 212.6- 214C. (dec.), as a White amorphous powder.

Example LV A mixture of 4.5 parts l-oxo-4-phenyl8-[3-(4-fluoroi5bonzoyl) propyl] 2,4,8 triaza spiro(4,5)decane, 0.5 part sodiumtetrahydridoborate, 48 parts tetrahydrofurane and 1 part distilled wateris stirred and refluxed for four hours. After cooling, the reactionmixture is decomposed with diluted hydrochloric acid and alkalized withammonium hydroxide. The aqueous layer is separated and extracted withchloroform. The combined organic layers are dried over magnesium sulfateand evaporated. The solid residue is boiled in parts methanol. Theundissolved part is filtered off while hot, yielding the product (mainlyunreacted l-oxo-4- phenyl 8 [3 (4 fiuorobenzoyl) propyl] 2,4,8-triaza-spiro(4,5)decane). On cooling the filtrate at room temperature, asecond fraction of 2 parts solid is filtered oif. The filtrate isevaporated. This residue (0.5 part), together with the second fractionof 2 parts product is recrystallized from 16 parts 2-propanol andfiltered. On keeping the filtrate at room temperature, dl 1 oxo 4 phenyl8 [4 (4 fluorophenyl) 4- hydroxybutyl] 2,4,8 triaza spiro(4,5)decane isobtained, melting point 175.5-l77 C., as a white microcrystallinepowder.

Example LVI A mixture of 5 parts 4-chloro-4'-methoxy-butyrophenone, 5parts 1-oxo-4-phenyl-2,4,S-triaza-spiro(4,5)decans, 4 parts sodiumcarbonate and a few crystals of potassium iodide and 200 parts4-methyl-2-pentanone is stirred and refluxed for forty-eight hours.After cooling, parts Water are added. The organic layer is separated,dried, filtered and evaporated. The oily residue is dissolved in 40parts 2-propanol. After cooling to room temperature the crude product isobtained. This crop is recrystallized from 24 parts 4-methyl-2-pentanone, yielding 1 oxo 4 phenyl 8 [3 (4- methoxybenzoyl) propyl]2,4,8 triaza spiro(4,5)decane, melting point l78.4l80 C., as a palebrown crystalline powder.

Example LVII To a stirred and refluxing solution of 6.7 parts l-oxo- 4cyclohexyl 2,4,8 triaza spiro(4,5)decane dihydrochloride and 8.5 partssodium carbonate in parts 4-methyl-2-pentanone is added dropwise asolution of 6 parts 4-chloro-4'-fiuoro-butyrophenone in 80 parts4-methyl-2-pentanone. After the addition is complete, the whole isstirred and refluxed for forty-eight hours. After cooling, the reactionmixture is decomposed with water. The organic layer is dried over sodiumsulfate and evaporated. The residue is dissolved in anhydrous ether andgaseous hydrogen chloride is introduced into the solution. Theprecipitated hydrochloride is filtered off and dried, yielding the crudeproduct. This crop is boiled in 80 parts 2-propanol. After cooling, 3.5parts of a mixture of the mono and dihydrochloride salt are obtained.This crop is triturated in boiling acetone and gaseous hydrogen chlorideis introduced into this mixture. The obtained solid is filtered off anddried, yielding l oxo 4 cyclohexyl 8 [3 (4 fluoro benzoyl) propyl] 2,4,8triaza spiro(4,5)decane dihydrochloride, melting point 206-215 C.(dec.), as beige granules.

Example LVIII To a stirred and refluxing solution of 6 parts 1-oxo-2-methyl-4-phenyl-2,4,S-triaza spiro(4,5)decane hydrochloride, 4 partssodium carbonate and a few crystals of potassium iodide in 104 parts4-methyl-2-pentanone is added dropwise a solution of 6 parts4-chloro-4'-fiuoro-butyrophenone in 56 parts 4-methyl-2-pentanone. Afterthe addition is complete, the whole is stirred and refluxed forforty-eight hours. After cooling, 100 parts water are added. The organiclayer is separated, dried over magnesium sulfate, filtered andevaporated. The oily residue is dissolved in parts diethylether andgaseous hydrogen chloride is introduced into the solution. Theprecipitated hydrochloride is filtered off and boiled in 56 parts 17Z-propanol. The undissolved part is filtered off from the hot solutionand dried to yield l-oxo-2-methyl-3-phenyl-8-[3-(4-fluorobenzoyl)-propyl]-2,4,8 triaza spiro(4,5) decanehydrochloride, melting point 252-254 C., as a white amorphous powder.

Example LIX Example LX A mixture of 4 partsl-o-xo-4-phenyl-8-[3-(4-fluorobenzoyl)-propyl]-2,4,S-triaza-spiro(4,5)decane,6.5 parts ropionic acid anhydride and 80 parts anhydrous toluene ,isheated to reflux. The obtained solution is stirred and refluxed forfifteen hours. The reaction mixture is filtered while hot. Aftercooling, the filtrate is alkalized with ammonium hydroxide. washed twicewith a 10% potassium carbonate solution,

dried over potassium carbonate, filtered and evaporated. "The oilyresiduesolidifies on treating in dissopropylether,

yielding 1-oxo-2-propionyl-4-phenyl-8-[3 (4fiuorobenzoyl)-propyl]-2,4,8triaza-spiro(4,5)decane, melting point86.5-88" C., as a beige granular powder.

Example LXI To a mixture of 44 parts l-benzyl-4-hydroxypiperidinesodium, 70 parts water and 40 parts alcohol are added dropwise 14 partsaniline (slightly exothermic reaction). After stirring for two hours, aprecipitate is formed. A solution of 9.5 parts potassium cyanide in 50parts water is added dropwise at room temperature, whereupon theprecipitate is dissolved again. After stirring overnight at roomtemperature, the Whole is extracted with 640 parts ether, the etherealsolution is Washed with about 1500 parts water, dried over K CO filteredand the filtrate is evaporated. -.The oily residue is dissolved inanhydrous diisopropylether. After cooling forone day at -15 C., 4.5parts of product are filtered off. This crop is recrystallized fromether and a few drops of acetone are added. After cooling overnight atl' C., l-benZyl-4-cyano-4- N-anilinopiperidine is filtered off, meltingpoint 144.8- 146.2 C., as shiny crystal needles.

Example LXII A mixture of 190 parts 1-benzyl-4-oxo-piperidine, 93 partsaniline and 700 parts glacial acetic acid is cooled to 30 C. Then thereis added dropwise a solution of 71.6 parts potassium cyanide in 200parts water, at the same temperature (exothermic reaction: temperaturerises to 45 C.). After the addition is complete, the whole is stirredfor twenty hours at room temperature. The reaction mixture is pouredinto a mixture of 1300 parts ammonium hydroxide and 1000 parts crushedice. The whole is extracted with chloroform. The organic layer is dried,filtered and evaporated. The solid residue is washed withdiisopropylether and dried, yielding 1-benzyl-4-cyano-4-N-anilinopiperidine, melting point 143.5147 C.

Example LX111 A mixture of 5 partsl-benzyl-4-cyano-4-N-anilinopiperidine and 60 parts sulfuric acid 90% isheated for ten minutes at 70 C. in a water bath. The water bath isremoved and the Whole is stirred for another hour. The reaction mixtureis poured into ice-water. The aqueous solution is alkalinized withammonium hydroxide and extracted with chloroform. The organic layer isdried over magnesium sulfate, filtered and evaporated. The

The toluene layer is separated,

18 solid residue is stirred in 56 parts benzene, filtered off and dried,yielding l-benzyl-4-carbamoyl-4-N-anilinopiperidine, melting point186.8-1 8 8.2 C., as a White amorphous powder.

Example LXI V A mixture of 95 parts 1-benzyl-4-oxo-piperidine, 33.1parts potassium cyanide, 50 parts methyl-amine hydrochloride, 120 partswater and 48 parts ethanol isv stirred for sixty-six hours at roomtemperature. The reaction mixture is extracted with chloroform. Theorganic layer is dried over sodium sulfate and evaporated. The residueis dissolved in a mixture of 80 parts petroleum ether and 80 partsdiisopropylether. After cooling to 20 C.,

two fractions of l-benzyl-4-cyanor4-N-methyl-aminopiperidine arefiltered off, one having a melting point 63-64" C.- and the other amelting point 61.2-62' C.

Example LX V 20 parts 1 benZyl-4-cyano-4-N methyl-aminopiperidinc areadded to 90 parts sulfuric acid 90% (exothermic reaction; temperaturerises to 75 C.). The whole is stirred for fifty minutes. The reactionmixture is poured into icewater. The whole is alkalinized with ammoniumhydroxide while cooling: a precipitate is formed. The whole is extractedwith chloroform. The organic layer is dried over potassium carbonate andevaporated. The solid residue is recrystallized from diisopropylether,filtered off and dried, yielding 1benzyl-4carbamoyl-4-N-methyl-arninopiperidine, melting point 156-157 C.,as a white flaky powder.

Example LXVI To a cooled mixture(30 C.) of 192 parts 1-benzyl-4-oxo-piperidine, 120.5 parts S-methyl-aniline and 500 parts glacialacetic acid isadded dro-pwise a solution of8l.4 parts potassium cyanidein parts water, in the course of thirty minutes (exothermic reaction:temperature rises from 30 to 40 C.). The whole is stirred for twodays atroom temperature." The reaction mixture is poured into 1000 partscrushed ice, while stirring. The whole is alkalinized withi 1200' partsammonium hydroxide and extracted with about 3000 parts chloroform. Theorganic layer is dried ,over potassium carbonate and evaporated. Theoily residue is dissolved in 320 parts diisopropylether and stirred.After cooling to 0 C., the formed precipitate is filtered ofi', yieldingcrude 1-benzyl-4- cyano-4-N (3 methylanilino piperdine. This crop ispurified by recrystallization from diisopropylether, yielding pure1-benzyl-4-cyano-4-N-(3-methylanilino) piperi/dine, melting point95.5-97 C., as colorless shiny crystals.

Example LXVII A solution of 41 parts potassium cyanide in 75 parts wateris added dropwise to a stirred mixture of 9.6 partsl-benzyl-4-oxo-piperidine, 69 parts 3 methoxy aniline and 250 partsglacial acetic acid, while maintaining a temperature of 30 to 37 C.After the addition is complete, the wholeis stirred at room temperaturefor fortyeight hours. The reaction mixture is poured into 750 partscrushed ice. The whole is alkalinized with 600 parts ammonium hydroxideand extracted with chloroform.

The organic layer is dried over potassium carbonate and evaporated. Theoily residue is dissolved in 320 parts diisopropylether. On stirringthis solution, a solid is precipitated. After cooling to 0 C.,l-benzyl-4-cyano-4- N-(3 methoxy anilino) piperidine is obtained,melting point 97-98 C., as a white flaky powder.

Example LX VIII 134.4 parts l-benzyl-4-cyano4N-(3-methyl-anilino)-piperidine are added portionwise to 915 parts concen- The temperaturerises to 70 C. Stirring is prolonged for two hours until completesolution is effected. The solution is added-dropwise to a mixture of1000 parts ice and 1300 parts ammonia, with stirring and cooling in anice bath.

The alkaline mixture is extracted with 3 x 200 parts chloroform, thechloroform solutions dried over potassium carbonate, concentrated underreduced pressure on a waterbath to a volume of about 400 ml. Theprecipitate is filtered with suction to yield, after drying, a firstcrop of 1-benzyl-4-carbamoyl-4-N-(3-methyl anilino) piperidine, meltingpoint 115.4122 C. A second crop of less purel-benzyl-4-carbamoyl-4-N-(3-methyl-anilino)-piperidine, melting point111-1l3.2 C. is obtained by concentrating the filtrate of the first cropto dryness under reduced pressure on the water bath.

Example LXIX 95 parts l-benzy-4-oxo-piperidine, 61.5 parts4-methylaniline and 260 parts glacial acetic acid are stirred togetheruntil complete solution is effected. Then 40.5 parts potassium cyanidein 100 parts water are added dropwise at 40 C. The mixture is stirredfor seventy-two hours at room temperature and poured into a mixture of650 parts concentrated ammonia and 500 parts ice. Extraction with 3 x200 parts chloroform, drying of the collective chloroform solutions over20 parts potassium carbonate, filtration and evaporation of the solventunder reduced pressure on the water bath yields a residue, from which,after recrystallization from 150 parts diiospropylether,l-benzyl-4-cyano- 4-N-(4-methyl-anilino) piperidine, melting point 112-115 C. is obtained as white soft crystals.

, Example LXX 80 parts l-benzyl-4-cyan0-4-N(4-methyl-anilino)-piperidineand 450 parts sulfuric acid 90% are mixed with stirring. The temperaturerises quickly to 75 C. The .mixture is allowed to cool slowly to roomtemperature, poured into excess ammoniacal ice water and extracted with3 x 100 parts chloroform. The organic layers are collectively dried over30 parts potassium carbonate, filtered and the solvent evaporated underreduced pressure on the water bath. The solid residue is filtered on aBuchnerfilter, washed with 3 X100 parts diisopropylether and dried.l-benzyl-4-carbamoyl 4 N-(4 methyl-anil- -ino)-piperidine, melting point166-167.5 C., is obtained .as a white amorphous powder.

Example LXXI A mixture of 95 parts 1-benzyl-4-oxo-piperidine, 61.5 parts4-chloro-aniline and 260 parts acetic acid are stirred together untilcomplete solution is effected. 40.5 parts .4-chloro-aniline aredissolved in 100 parts water and this solution is added dropwise to theacetic acid solution, an exothermic reaction ensuing. After completeaddition, stirring is continued for forty-eight hours. The reactionmixture is poured into 500 parts ice and excess ammonia. Extraction with3 x 150 parts chloroform, drying over 20 pants potassium carbonate,filtration and evaporation of the solvent under reduced pressure on thewater bath yields a solid residue, which, after washing with 100 partsdi- .isopropylether and drying, yields 1-benzyl-4-cyano-4-N-v(4-chloro-anilino)-piperidine, melting point 157-159 C., as a whitegranular powder.

Example LXXII 96 parts 1-benzyl-4-oxo-piperidine, 60 partsZ-methylaniline and-260 parts glacial acetic acid are mixed while beingstirred and cooled. A solution of 41 parts potassium cyanide in 70 partswater is added dropwise. An exothermic reaction raises the temperatureof the mixture from 25 C. to 38 C. Stirring is continued for fortyeighthours after complete addition, after which time the reaction mixture ispoured into excess ammonia and ice. .The reaction product is extractedwith 3 x 100 parts chloroform and the combined extracts dried over 30parts potassium carbonate, filtered and evaporated under reducedpressure on a boiling water bath. The resulting oily residue is pouredinto 240 parts diisopropylether. On cooling at C. for two hours, acrystalline precipitate separates. These crystals filtered off anddried, yielding 20 1-benzyl-4-cyano-4-N-(Z-methyl-anilino)-piperdine,melting point 117-120" C., as a grey crystalline powder.

Example LXXIII parts l-benzyl-4-oxo-piperidine, 50 partscyclohexylamine, 50 parts concentrated hydrochloric acid, 65 partsethanol and 60 parts water are mixed while being stirred and cooled.Then a solution of 32.5 parts potassium cyanide in 40 parts water isadded dropwise. Stirring is continued overnight. Then 200 parts waterare added and the reaction mixture is extracted with 3 x 80 partschloroform. The combined extracts are dried over 25 parts sodiumsulfate, filtered and evaporated. The residue is dissolved in 280 partsdiisopropylether. Crystallization follows practically immediately atroom temperature, to yield1-benzyl-4-cyano-4N-cyclohexylaminopiperidine, melting point 8283 C., aswhite glistening crystals.

A second crop of l-benzyl-4-cyano-4-N-cyclohexyl aminopiperidine,melting point 7679 C., is obtained after further keeping the motherliquor at room temperature. Also a third and a fourth crop are obtainedhaving, respectively, melting point 7879 C. and melting point 73.4-74.8C.

Example LXXIV 20 parts 1-benZyl-4-cyano-4-N-cyclohexylaminopiperidineare added portionwise to parts sulfuric acid 90% in fifteen minutes. Thetemperature rises to 80 C. Stirring is prolonged for one hour untilcomplete solution is effected. The mixture is allowed to cool to roomtemperature, poured into excess ammoniacal ice water and extracted with3 x 75 parts chloroform. The combined organic layers are dried over 15parts potassium carbonate, filtered and the solvent is evaporated underreduced pressure on the water bath. The solid residue is washed with 3 x50 parts diisopropylether, filtered and dried to yield1-benzyl-4-carbamoyl-4-\ -cyclohexylaminopiperi- .dine, melting pointl38.8-139.6 C., as a white amorphous powder.

A second crop of 1-benzyl-4-carbamoyl-4-N-cyclohexylaminopiperidine isobtained by further crystallization of the mother liquor at roomtemperature, melting point l47148 C.

Example LXX V 5 8 partsl-benzyl-4-N-(4-chloro-anilino)-4-cyanopiperidine are added portionwiseto 276 parts sulfuric acid 90% (exothermic reaction). After the additionis complete,

the whole is heated to 70 C. for ten minutes. Then the.l-benzyl-4-carbamoyl-4-N-(4-chloro-anilino) piperidine,

melting point 172l73 C., as a white granular powder.

Example LXXVI To 400 parts sulfuric acid 98% are added portionwise, inthe course of twenty minutes, 64 parts 1-benzyl-4-cyano-4-N(3-methoxy-anilino)piperidine, while stirring (exothermicreaction: the temperature rises from 20 to 60 C.). Stirring is continuedfor ten minutes at 70 C., whereupon the reaction mixture is cooled toroom temperature, while stirring, in the course of two hours. The Wholeis poured into 750 parts ammonium hydroxide and 750 parts crushed ice.The mixture is extracted with chloroform. The organic layer is driedover postassium carbonate and then evaporated. The oily residue isdissolved in 160 parts toluene. After cooling to 0 C., 1-benzyl-4-carbamoyl-4-N-(3-methoxy-anilino) piperidine is filtered off,melting point -131 C.

Example LXXVII To 375 parts sulfuric acid 98% are added portionwise 214'7 parts 1-benzyl-4-cyano-4-N-(Z-methyl-anilino)-piperidine, in thecourse of thirty minutes, While stirring. After the addition iscomplete, the Whole is stirred first at room temperature for fifteenminutes while cooling (exothermic reaction: temperature rises from 15 to43 C.), and then at a temperature of 70 C. for fifteen minutes. Aftercooling to room temperature, the mixture is poured into a .mixture of1000 parts ammonium hydroxide and 1000 parts crushed ice. The whole isextracted with 2000 parts chloroform. The organic layer is separated,dried over potassium carbonate and evaporated. On treating the oilyresidue with 240 parts diisopropylether, a precipitate is formed. 3After cooling overnight at C., 1-benzyl-4-carbamoyl-4-N-(2-methyl-anilino)-piperidine is filtered off, meltingpoint 126128 C.

Example LXXVIII To a stirred mixture of 95 partsl-benzyl-4-oxo-piperidine, 36.5 parts n-butylamine and 48 parts ethanolare added dropwise 50 parts concentrated hydrochloric acid at atemperature below 20 C. (ice bath). After the addition is complete,there is added dropwise a solution of 33.1 parts potassium cyanide in120 parts water, while maintaining this temperature. After the additionis comture for two days a second crop' and a third crop of the finalproduct are obtained, having, respectively, melting 1 point 75-77 C., asWhite crystals and melting point Example LXXIX To 108 parts sulfuricacid'98% are added portionwise 20 parts1-benzyl-4-cyano-4-N-(butylamino)-piperidine, in the course of twominutes, while stirring (exothermic reaction: temperature rises to-60C.). After the addition is complete, the whole is heated at 80 C. forone hour-whilestirring and thencooled to room temperature. The reactionmixture is poured into ice and ammonium hydroxide. An oil isprecipitated. The whole is extracted with chloroform. The organic layeris dried over potassium carbonate, filtered and evaporated. The residueis dissolved in 40 parts diisopropylether. After cooling overnight at l5C., crude 1-benzyl-4-carbamoyl-4-N- (butylamino)-piperidine is obtained.A sample of 3 parts is recrystallized from 24 parts isopropanol.overnight at -15 C., 1-benzyl-4 carbamoyl-4-N-(butylamino)-piperidine isfiltered oif, melting point 114118 C., as a white amorphous powder.

Example .LXXX

A mixture of 950 parts- 1-benzyl-4-oxo-piperidine, 694 parts of4-methoxy-aniline and 2500 parts glacial acetic acid is cooled to 25 C.Then. there are added dropwise 405 parts potassium cyanide 'in 800 partswater..

After the addition is complete, the whole is stirred for forty-eighthours at room temperature. The reaction mixture is poured into a mixtureof 5000 parts crushed ice and 5000 parts ammonium hydroxide. The Wholeis extracted with 11,000 parts chloroform. The organic layer isseparated, driedand evaporated. The residue is re- After cooling.

crystallized fromether to yield 1-be'nzyl-4-cyano-4-N-(4-methoxyanilino)-piperidine, melting point 110-117 C.

Example LXXXI reaction mixture is poured into 400 parts water.

' dissolved in 400 parts petroleum ether.

overnight at room temperature, crude l-benzy1-4-cyan0- C. After theaddition is complete, the reaction mixture is cooled to 60 C., thenpoured into a mixture of 12,000 parts crushed ice to which 14,000 partsammonium hydroxide are added. The whole is extracted with chloroformwhile hot. The organic layer is separated, dried over sodium sulfate,filtered and evaporated. The .oily residue is poured into 800 partsdiisopropylether. The precipitated solid is filtered off and trituratedin diisopropyiether, to yield1-benzyl-4-carbamoyl-4-N-(4-methoxyanilino)-piperidine, melting point131134 C.

Example LXXXII To a mixture of parts 1-benzyl-4-oxo-piperidine and 48parts denaturated ethanol are added portionwise 22.5 parts ethylamine,at a temperature below 20 C. (cooling with an ice bath). Whilemaintaining this temperature, there are added first 50 partsconcentrated hydrochloric acid, followed by 33.1 parts potassiumcyanideand parts water. After the addition is complete, the Whole is stirredfor five days at room'temperature. The The whole is extracted withchloroform. The organic layer is washed with 1000 parts Water, driedover potassium carbonate, filtered and evaporated. The oilyresidue isdissolved in 240 parts petroleum ether. After cooling for twenty-fourhours at -15 C., crude 1-henzy114 cyano- 4-N- (ethylamino)-piperidine isobtained. This'crop is recrystallizedfrom 40 parts ether. After coolingto 0 C., 1 benzyl 4 cyano-4-N-(ethylarnino)-piperidine isobtained,melting point 55-56" C., as shiny crystals.

Example LXXXIII 48 parts denaturated ethanol are added portionwise 53parts isopropylarnine hydrochloride, at a temperature below 20 C.(cooling with ice-bath). While maintaining this temperature, there areadded 33.1 parts potassium cyanide in 120 parts water. After theaddition is complete, the whole is stirred at room temperature. Afterabout fifteen minutes a solid mass-is obtained. Then there are added 48parts ethanol and 120 parts water. After further stirring overnight atroom temperature, the reaction mixture is dilutedwith 200 parts water.The whole is extracted with chloroform. The organic layer is separated,washed with 1000 parts Water, dried over sodium sulfate, filtered andevaporated. The residue is After keeping 4-N(2-propylamino)-piperidineis obtained. This crop is recrystallized from 48 parts ether. Aftercooling to 0 .C., 1-benzyl-4-cyano-4-N-(2-propylamino)-piperidine isfiltered off, melting point 6467 C., as a white amorphous powder.

On keeping the first mother liquor for two days at room temperature, asecond fraction of less pure l-benzyl-4-cyano-4-N-(2-propylamino)-piperidine is obtained, melt ing point 59-64C.

Example LXXXIV 66 parts 1-benzyl-4-cyano-4-N-(ethylamino)-piperidine areadded portionwise to 432 parts sulfuric acid 98% (exothermic reaction:temperature rises from 16 to 81 C.). After the addition is complete, thewhole is stirred for one hour. The reaction mixture is poured into amixture of crushed ice and ammonium hydroxide. The whole is extractedwith chloroform. The organic layer is separated, dried over potassiumcarbonate, filtered and evaporated under reduced pressure. The residueis triturated in ether, yielding1-benzyl-4-carbamoyl-4-N-(ethylarnino)-piperidine, melting point113.61l5.4 C.

0n recrystallization of a sample of this crop from a mixture of 24 partsether and 40 parts ethanol, the compound has a melting point of115.2-1192" C., as white crystals.

i solved in ether.

23 Example LXXXV 64 parts1-benzyl-4-cyano-4-N-(2-propylamino)-piperidine are added portionwise to434 parts sulfuric acid 98%, while stirring (exothermic reaction:temperature rises from 18 to 79 C.), After the addition is complete, thewhole is stirred for one hour. The reaction mixture is poured into amixture of crushed ice and ammonium hydroxide. The whole is extractedwith chloroform. The organic layer is dried over potassium carbonate,filtered and the filtrate is evaporated, yielding 52 parts crudeproduct. This crop is recrystallized from a mixture of 24 parts etherand 40 parts ethanol. After cooling for two days to C.,1-benzyl-4-carbamoyl-4-N-(Z-propylamino)-piperidine is obtained, meltingpoint 117.8- 120.4 C., as white shiny crystals.

Example LXXXVI To a stirred mixture of 95 parts1-benzyl-4-oxo-piperidine, 29.5 parts propyl amine and 48 partsdenaturated ethanol are added dropwise 50 parts concentratedhydrochloric acid at a temperature below C. After the addition iscomplete and while keeping the temperature below 20" C., there is addeddropwise a solution of 33.1 parts potassium cyanide in 120 parts water.After the addition is complete, the whole is stirred for three days atroom temperature. The reaction mixture is poured into 200-parts waterand then extracted with chloroform. The organic layer is washed withwater, dried over potassium carbonate, filtered and evaporated. An oilyresidue of crude 1-benzyl-4-cyano-4-N-(propylamino)-piperidine isobtained. It is used without further purification for preparing 1benzyl-4-carbamoyl-4-N-(propylamino) piperidine.

Example LXXXVII To 165 parts sulfuric acid 98% are added 25.7 parts1-benzyl-4-cyano-4-N (propylamino) piperidine While stirring (exothermicreaction: temperature rises from 18 to 82 C.). The Whole is stirred forone hour (temperature falls to 26 C.). The reaction mixture is pouredinto a mixture of crushed ice and ammonium hydroxide. The Whole isextracted with chloroform. The organic layer is separated, dried overpotassium carbonate, filtered and evaporated under reduced pressure. Theresidue is dis- After keeping at room temperature, 1-benzyl-4-carbamoyl-4-i -(propylamino)-piperidine is filtered off,melting point 128-131 C., as a white crystalline powder.

Example LXXXVIII A mixture of 6.2 parts1-benzyl-4-carbamoyl-4-N-anilinopiperidine, 3.1 parts actic acidanhydride and 40 parts anhydrous toluene is stirred and refluxed forsixteen hours. After cooling the reaction mixture is decomposed withwater, followed by addition of ammonium hydroxide. The aqueous layer isseparated and extracted once more with toluene. The combined organiclayers are dried over potassiumcarbonate and evaporated. The

oily residue is dissolved in 200 parts diethylether. This solution isfiltered several times, until clear and then hydrogen chloride gas inintroduced into the filtrate. The precipitated hydrochloride is filteredoff and stirred in a warm mixture of acetone and isopropanol. Theundissolved part is filtered off, yielding 1.5 parts product. From thiscrop the free base is liberated in the usual manner. After extractionwith benzene, the organic layer is dried and evaporated. The residue iswashed with ether and dried, yielding1-oxo-3-methyl-4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)dec-2-ene,melting point 211.5 214.5 C., as a beige, crystalline powder.

Example LXXXIX A mixture of 9.8 parts1-benzyl-4-carbamoyl-4-N-methylaminopiperidine and 60 partstriethoxy-methane is refluxed for eighteen hours with stirring. Thereaction mixture is evaporated to dryness under reduced pressure on theWater bath and the residue taken up in parts boiling ethyl acetate. Theprecipitate is filtered on a Buchner filter and dried to yield1-oxo-4-methyl-8-benzyl-2,4,8- triaza-spiro(4,5)dec-Z-ene, melting point178179.5 C., as glistening crystals.

A second crop of less pure 1-oxo-4-methyl-8-benzyl-2,4,8-triaza-spiro(4,5)dec-2-ene is obtained after cooling the motherliquor overnight at -5 C., melting point 175-178.5 C.

7 Example XC A mixture of 14.9 parts 1-oxo-3-methyl-4-phenyl-8benzyl-2,4,S-triaza-spiro(4,5)dec-Z-ene and 160 parts ethanol isdebenzylated at normal pressure and at a temperature of 37-39 C., in thepresence of 5 parts palladium-on-charcoal catalyst 10%. After thecalculated amount of hydrogen is taken up, hydrogenation is stopped. Thecatalyst is filtered off, washed with 2 x 50 'parts ethanol and thecombined ethanol solutions are evaporated. The solid residue, afterwashing with 150 parts ether, and drying, yieldsl-oxo-3-methyl-4-phenyl- 2,4,8-triaza-spiro(4,5)dec-2-ene, melting point197.4- 205 C.

Example XCI A mixture of 66.7 parts 1-benzyl-4-carbamoyl-4-N-anilinopiperidine, 30 parts triethoxy-methane, 280 parts toluene and 16parts glacial acetic acid is stirred and refluxed for thirty-eighthours. After cooling, the reaction 'mixture is decomposed with 20 partsammonium hyroxide and 50 parts water. The organic layer is separated,dried over magnesium sulfate and filtered. On standing, a precipitate isformed, which is filtered off and dried, yielding 4 parts of1-benzyl-4-carba1noyl-4-N- anilinopiperidine. The mother liquor isconcentrated to a volume of about parts. After keeping at roomtemperature, 45 parts crude product are obtained. This crop is dissolvedin 48 parts toluene. After cooling to room temperature,1-oxo-4-phenyl-8-benzyl-2,4,8-triazaspiro(4,5)dec-2-ene is obtained,melting point 171.2- 173.2 C., as yellow shiny crystals.

Example XCII A mixture of 15parts1-benzyl-4-carbamoyl-4-N-cyclohexyl-amino-piperidine, 15 partstriethoxy-methane, 120 parts toluene and 4 parts glacial acetic acid isstirred and refluxed for forty-two hours. After cooling the reactionmixture is evaporated. The residue is dissolved in Water. The aqueoussolution is alkalinized with ammonium hydroxide and extracted withchloroform. The organic layer is dried over sodium sulfate andevaporated. The residue is recrystallized twice from ethyl acetate, toyield 1- oxo-4-cyclohexyl-8-benzyl-2,4,8-triaza spiro (4,5 dec-2- ene,melting point 209211.4 C.

Example XCIII Example XCI V A mixture of 27.5 parts1-benzyl-4-carbamoyl-4-N-(2- propylamino)-piperidine, 55 partstriethoxymethane, 80 parts toluene and 10 parts glacial acetic acid isstirred and refluxed for two days. After cooling, the reaction mixtureis evaporated. The oily residue is alkalinized with sodium hydroxide andthen extracted with chloroform. The organic layer is separated, driedover potassium carbonate,

Example X C V A mixture of 2 6 1 parts11benzyl-4-carbamoyl-4-N-(butylamino)-piperidine, ,50 partstriethoxy-methane, 80 parts toluene and 9 ,parts glacialacetic acid isstirred and ;refluxed for two days. After cooling the reaction mixtureis evaporated under reduced pressure. The residue is alkalinized andextracted with chloroform. .T he organic layer is separated, dried overpotassium carbonate, filtered and evaporated. The residueisrecrystallized from 180 parts ethyl acetate, yielding '14 parts product.This crop is recrystallized from ,1'60'parts ethyl acetate, yielding 9.5parts product. T his crop is dissolved in a mixture of 160 partsanhydrous ether and 40parts 2-propanol and gaseous hydrogen chloride isintroducedintpthe solution. After cooling overnight at C.,1-oxo-4-butyl-8-benzyl 2,4,8- triaza-spiro(4,5)dec-2-ene-dihydrochlorideisfiltered off, melting point 265-267.5 C., as a white granular powder.

Example XCVI A mixture of 20 parts 1-oxo-4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)decane, 200 parts methanol, 40 parts isopropanol and 7parts concentrated hydrochloric acid is debenzylated at normal pressureand at a temperature of 38 to 40 C., in the presence of 10 partspalladium-oncharcoal catalyst. After the calculated amount of hydrogenis taken up, hydrogenation is stopped. The catalyst is filtered oif andthe solvent is evaporated. The residue is dissolved in water. Thisaqueous solution is alkalinized with ammonium hydroxide and extractedwith chloroform; The organic layer is dried over magnesium sulfate,filtered and evaporated. The solid residue is washed with ether,filtered ofr" and dried, yielding l-oxo- 26 E pl .XCIX

A mixture of 24 parts 1-oxo-4-(3-methyl-phenyl)-8- benzyl-2 ,4,8-triaza-spiro(4,5)decane, 320 parts methanol and 20 parts concentratedhydrochloric acid is debenzylated at normal pressure and at atemperature of about 50 C., in thepresence of 10 partspalladium-on-charcoal catalyst. After the calculated amount of hydrogenis taken up, hydrogenation is stopped. The catalyst is filtered off andextracted with boiling-water. The combined filtrates are evaporated andto the solid residues is added a small volume of ammonium hydroxide andthe mixture is extracted withchloroform. The organic layer isseparated,.dried, filtered and evaporated. Th Solid residue is-stirredin diisopropylether, filtered oil and dried, yielding 1-oxo-4- (3-methylpheny1.)a2,4,8-triaza spiro (4,5 decane, melting point 189.'8-190.8 C.

Example C mal pressure and at atemperature of about 40 C., in thepresence of 7 parts palladium-on-charcoal catalyst. After the calculatedamount of hydrogen is taken up, hydrogenation is stopped. Then 200 partswater are added. The catalyst is filtered oif and the filtrate isconcentrated under diminished pressure. The residue is alkalinized withammonium hydroxide. The whole is extracted with about 1500 partschloroform. The organic layer is dried over potassium carbonate andconcentrated to a volume of about '60 parts. During this evaporation asolid is V precipitated. It is filtered oil and dried to yield 1-0xo-4-4-phenyl-2,4,8-triaza-spiro(4,5 decane, melting point 168- Example XCVIIA mixture of 18 parts 1-oxo-4-methyl-8-benzyl-2,4,8-triaza-spiro(4,5)dec-Z-ene, 40 parts Z-propanol, 200 parts methanol and7 parts hydrochloric acid is debenzylated at normal pressure and at atemperature of 27 C., in the presence of 10 parts palladium-on-charcoalcatalyst. After the calculated amount of hydrogen is taken up,hydrogenation is stopped. The charcoal is filtered 01f and the filtrateis evaporated. The residue is recrystallized from boiling acetone, theformed precipitate is filtered off again and dried, yielding 13 partsproduct. This crop is boiled once more in 240 parts 2-propanol, filteredand dried, yielding1-oxo-4-methyl-2,4,8-triaza-spiro(4,5)decane-hydrochloride, meltingpoint 200-203 C., as a white amorphous powder.

On keeping the mother liquor :at room temperature, a

" second less pure crop of 1-oxo-4-methyl-2,4,S-triaza-spiro ExampleXCVIII A mixture of 35 parts 1-oxo-4-(4-methyl-phenyl)S-benzyl-2,4,8-triaza-spiro(4,5)decane, 320 parts methanol and 20 partsconcentrated hydrochloric acid is debenzylated at normal pressure and ata temperature of about 50 C., in the presence of 10 partspalladium-on-charcoal catalyst. After the calculated amount of hydrogenis taken up, hydrogenation is stopped. The charcoal is filtered off andthe filtrate is evaporated. The solid residue is dissolved in water. Theaqueous solution is alkalinized with ammonium hydroxide and extractedwith warm chloroform. The organic layer is separated, dried, filteredand evaporated. The solid residue is stirred in diethylether, filteredoff again and dried, yielding 1-oxo-4-(4-methyl-phenyl)-2,4,8-triaza-spiro(4,5)decane, melting point 190-1914 C., as apale-grey, amorphous powder.

( 4-methoxy-phenyl -3,4,8-tn'aza-spiro (4,5 decane, melting point195-196" C., as a white micro-crystalline powder.

Example CI A mixture of 22 parts 1-oxo-4-cyclohexyl-S-benzyl- 2,4,8-triaza-spir0(4,5)dec-Z-ene, 160 parts methanol, 245 parts 2-propanol and 7parts concentrated hydrochloric acid is hydrogenated at normal pressureand at room temperature, in the presence of 15 partspalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen (2 moles) is taken up, hydrogenation is stopped. The catalystis filtered ofiF. After keeping the filtrate at room temperature, asolid is precipitated. It is filtered and dried, to yield crude1-oxo-4-cyclohexyl-2,4,8-triaza-spiro (4,5)decane dihydrochloride,melting point 205-220 C.

Example CII A mixture of 9 parts 1-oxo-3-methyl-4-phenyl-2,4,8-triaza-spiro(4,5)dec-Z-ene and parts methanol is hydrogenated at normalpressure and at a temperature of about 37 C., in the presence of 0.2parts platinum oxide as catalyst (Adams catalyst). After the calculatedamount of hydrogen is taken up, hydrogenation is stopped. The catalystis filtered 01f. After cooling the filtrate to 0 C.,dl-1-oxo-3-methyl-4-phenyl-'2,4,8-triaza-spiro(4, 5 )decane is filteredoff, melting point 196.2-199.2 C.

The mother liquor is concentrated to a volume of about 30 parts,whereupon a solid is precipitated. The whole is diluted with 40 parts2-propano1. The product is filtered off, yielding a second fraction ofdl-1-oxo-3- methyl 4 phenyl 2,4,8 triaza spiro(4,5)decane, melting point196197.5 C.

Example CIII A mixture of 13 parts 1-oxo-2-methyl-4-phenyl-8-benzyl-2,4,8-triaza-spiro(4,5)-decane 80 parts methanol and 24 partsZ-propanol is debenzylated at normal pressure and at a temperature ofabout 35 C., in the presence of 4 parts palladium-on-charcoal catalyst.After the calculated amount of hydrogen is taken up, hydrogenation isstopped. The catalyst is filtered oil and the filtrate is evaporated.The oily residue is dissolved parts diethylether and gaseous hydrogenchloride is in troduced into the solution. The precipitatedhydrochloride is filtered off and dissolved in 48 parts 2-propanol. Thedissolved part is filtered off, yielding l-oxo-Z-rnethyl- 4 phenyl 2,4,8triaza spiro(4,5)decane hydrochloride, melting point 205-209 C., as awhite microcrystal- .line powder. 7

Example CI V A mixture of 20 parts of 1-oXo-4-(2-propyl)-8-beuzyl-2,4,8-triaza-spiro(4,5)dec-Z-ene, 160 parts Z-propanol,

'200 parts distilled water and 15 parts concentrated hydrochloric acidis hydrogenated at normal pressure and at a temperature of about 30 C.,in the presence of 7 parts palladium-on-charcoal catalyst. After thecalculated amount of hydrogen is taken up, hydrogenation is stopped. Thecatalyst is filtered off and the filtrate is evaporated. The residue isalkalinized with sodium hydioxide and extracted with chloroform. Theorganic layer is dried, filtered and evaporated, yielding 1-oxo-4- 282-propyl) -2,4,8-triaza-spiro(4, 5 decane, melting point 158-161 C.

What is claimed is:

1. 1-benzyl-4-R -4-NHR -piperidine wherein R is a member selected fromthe group consisting of cyano and carbamoyl and NHR is a member selectedfrom the group consisting of anilino, lower alkylanilino, loweralkoxyanilino, chloroanilino, lower alkylamino, cyclohexylamino'andhaloanilino, the lower alkyl and lower alkoxy substituents containingfrom 1 to 6 carbon atoms.

2. 1-benzyl-4-cyano-4-N-anilinopiperidine.

3. 1-benzyl-4carbamoyl-4-N-anilinopiperidine.

4. 1 benzyl 4 cyano 4 N (3 methylanilino)- piperidine.

5. 1 benzyl 4' carbamoyl 4 N (3 methylanilino)-piperidine.-' s

4 6. 1-benzyl-4-cyanoe-4 N-methyl-aminopiperidine.,

7. 1-benzyl-4-carbamoyl-4-N-methylaminopiperidine.

8. 1-benzyl-4-cyano-4-'N-(Z-propylamino)-piperidine.

9. 1 benzyl 4 carbamoyl 4 N (2-propylamino)- piperidine.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,161,644 December 15, 1964 Paul Adriaan Jan Janssen It is herebycertified that error appears in the above numbered patent requiringcorrection and that the said Letters Patent should read as correctedbelow.

Column 3, line 13, for "l-oxophenyl" read l-oxo-4- pheny'l column 10,line 62, for "(4.5)" read (4,5)

column 15, line 66 for "(denatured)" read (dienaturated) column 16, line1, for "bonzoyl)-" read benzoyl) column 18, line 46, for"-methylanilinopiperdine" read methylanilino)piperdine column 23, line51, for "actic" read acetic line 60, for "in" read is column 26, line 34for "3,4,8" read -2,4,8 column 27, line 3, for "-triza" read triazaline8, for "dissolved" read undissolved same column 27, line 13, strike out"of".

Signed and sealed this 6th day of July 1965.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Aitcsting Officer Commissioner ofPatents

1. 1-BENZYL-4-R1-4-NHR2-PIPERIDINE WHEREIN R1 IS A MEMBER SELECTED FROMTHE GROUP CONSISTING OF CYANO AND CARBAMOYL AND NHR2 IS A MEMBERSELECTEDFROM THE GROUP CONSISTING OF ANILINO, LOWER ALKYLANILINO, LOWERALKOXYANILINO, CHLOROANILINO, LOWER ALKYLAMINO, CYCLOHEXYLAMINO ANDHALOANILINO, THE LOWER ALKYL AND LOWER ALKOXY SUBSTITUENTS CONTAININGFROM 1 TO 6 CARBON ATOMS
 2. 1-BENZYL-4-CYANO-4-N-ANILINOPIPERIDINE.